Ovarian Clear Cell Carcinoma
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1 Ovarian Clear Cell Carcinoma Rouba Ali-Fehmi, MD Professor of Pathology The Karmanos Cancer Institute, Wayne State University School of Medicine
2 50 year old woman with chief complaint of shortness of breath As part of her work up; PE abdominal pain and abdominal distention. Imaging study: cystic right adnexal mass with solid and cystic features. Patient underwent surgical resection.
3 Intraoperative Findings Right adnexal mass: 340 g, 9 x 8 x 6 cm, partially cystic, filled with bloody fluid.. The right fallopian tube was unremarkable.
4
5 Frozen Section Diagnosis:
6 Frozen Section Diagnosis: serous carcinoma
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9 Final Diagnosis: Clear Cell Carcinoma
10 Clear Cell Carcinoma Most common cause for error at frozen section & permanent section in gynecologic pathology Often low mitotic index May not show marked nuclear atypia May not have clear cells Lots of other tumors have clear cells
11 Clear Cell Carcinoma Second most common surface epithelial carcinoma Associated with endometriosis ovarian and/or pelvic Almost always unilateral (>95%) Increased risk thromboembolism (x2.5) Poor response to cis-platinum therapy Presents in premenopausal age group as well as postmenopausal
12 Clear Cell Carcinoma Grossly
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14 Ovary: Heterotopias Endometriosis
15
16 Clear Cell Carcinoma Papillary Tubulocystic (or glandular) Cystic Solid Often prominent hyalinized stroma or spherule-like mucoid stroma Fibromatous, fibroblastic, edematous stroma
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25 Clear Cell Carcinoma Hobnail cells Clear or eosinophilic granular cytoplasm (glycogen) Signet ring cells containing mucin
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31 CCC Associated with endometriosis ovarian and/or pelvic Cohort study in Denmark ( ) Increased risk of OC in women with endometriosis restricted to 2 histologies Endometrioid (RR, 2.53; 95%CI ) Clear cell (RR, 3.37; 95% CI ) Brinton et al. Cancer Epidemiol Biomar Prev 2005;14:
32 CCC Associated with endometriosis ovarian and/or pelvic Endometriosis in up to 70% Atypical endometriosis may be seen adjacent to clear cell carcinoma
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37 PTEN in Ovarian CCC PTEN inactivation may be early event in malignant transformation of endometriosis Mutations occur in both endometrial and ovarian carcinomas Histology Endometriotic Ovarian Cyst Endometrioid EOC Clear Cell EOC Inactivation (LOH) 13/23 (56.6%) 8/19 (42.1%) 6/22 (27.3%) Somatic PTEN Mutation 5/23 (20.6%) 4/19 (20%) 2/22 (8.3%) Sato et al. Cancer Res 2000;60:7052-6
38 At the molecular level
39 ARID1A AT-rich interactive domain 1A gene Tumor suppressor gene Encodes for BAF250a protein Plays critical role in SWI-SNF chromatin remodeling complex present in all eukaryotes Responsible for regulating critical cellular processes and gene expression
40 ARID1A in Ovarian CCC 50% of CCC and 30% of EC have mutations No proven clinical features/differences in outcomes associated with reduction/loss of expression of BAF250a by IHC
41 PIK3CA Mutations in Ovarian CCC Frequently co-mutated with ARID1A in CCC Observed in up to 40% of CCC Activation of PI3K AKT mtor-hif pathway Role of PI3K-mTOR inhibitors?
42 Ovarian Clear Cell Carcinoma IHC
43 IHC Negative ER, (90%) WT1, (85%) CK20, (95%) BAF250a, (20%) P53, (>85%) Positive HNF1β, (85%) Napsin A, (88%) CK7, (95%) PAX8, (85%) PAX2, (7%)
44
45 HNF1-β
46 PAX8
47 Diagnostic Reproducibly Diagnosis Kappa Translation Clear Cell Ca (CCC) 0.82 Excellent Serous Ca (SC) 0.59 Moderate Mixed Serous-Clear Ca (MSCC) 0.32 Fair Am J Surg Pathol 2008;32:955-64
48 ER- WT1- ER+ WT1+ Mixed CCC/S-CA rare, but they exist!
49
50 Grade in CCC Most exhibit range of nuclear atypia but some feature only low to moderate pleomorphism Mitotic index variable often low Architecture varies from well developed papillae to sheets of cells But, to date, no evidence that grading (nuclear, architecture, mitotic index) stratifies outcome
51 CCC: Cystic vs Adenofibromatous Adenofibromatous tumors may be better, but is this reflection of borderline, low stage cases? Cystic tumors may be better, but is this reflection of low tumor volume? Endometriosis tumors probably not better, but may be worse for mixed tumors (this may be reflection of stage)?
52 Ovarian Clear Cell Carcinoma: Diagnostic Problems Epithelial tumor: Borderline clear cell tumor Serous carcinoma Endometrioid carcinoma Mucinous carcinoma Mixed surface epithelial carcinoma Borderline serous tumor Germ line tumor: Yolk sac tumor Dysgerminoma Sex cord stromal tumor: Metastasis (esp. renal cell):
53 Borderline Clear Cell Tumor One or two cell layers Minimal to mild atypia Prominent fibromatous stroma Mitotic figures <1/10 hpf VERY RARE
54
55 Quiz time!
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57 CCC HG Serous Ca
58 CCC Serous-CA Unilateral Hobnail cells Other patterns CCC WT1-, ER- HNF-1 beta+/- Bilateral Cytoplasmic clearing Other patterns S-CA WT1+, ER+ HNF-1 beta-/+
59 CCC vs. Ovarian Serous Carcinoma (SC) No convincing evidence that low stage CCC is more aggressive than low stage SC but low stage SC exceedingly rare High stage CCC does not respond to standard platinum-based therapy
60 Frozen Section Diagnosis:
61
62 Frozen Section Diagnosis: At least serous borderline tumor
63 Final Diagnosis: Clear Cell Carcinoma
64 Papillary CCC versus SBT Both may occur in younger patient population (reproductive age) May result in inadequate or delayed staging & therapy Requires extensive sectioning to determine correct diagnosis
65 CCC SBT Unilateral Monomorphic cell population Hobnail cells Endometriosis common Other patterns CCC WT1-/ER- Bilateral Mixed ciliated and pink cells Pink cell tufts Endometriosis uncommon Other patterns S-LMP WT1+/ER+
66
67 ??
68 CCC SBLT
69 Serous Borderline
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71 CAUTION: CCC can also be misdiagnosed as serous borderline tumor SBLT CCC
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73 Napsin, neg
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76 endometrioid CCC
77 CCC Endometrioid-CA Unilateral Hobnail cells Other patterns CCC WT1-, ER- HNF-1 beta+/- Unilateral, but may be bilateral Cytoplasmic clearing Other patterns E-CA WT1-, ER+ HNF-1 beta-/+
78 Endometrioid Carcinomas with Clear Cytoplasm Secretory carcinoma - subnuclear and supranuclear vacuoles, most of the time has low grade (nuclear grade 1-2) cytology Endometrioid carcinoma with clear cytoplasm, due to glycogen, lipid, other Squamous glycogenization has other areas of classic squamous differentiation
79 ??
80 CCC Yolk Sac Tumor
81 Intraoperative Consultation Issues In the reproductive years, misdiagnosing yolk sac for CCC is especially problematic. Yolk sac: Limited, reproductive conservation surgery is standard of care. Chemotherapy is highly effective. CCC: Full cancer staging operation
82 OVARY EST
83 OVARY Clear cell
84 Yolk Sac Tumor
85 CCC AFP, negative Yolk Sac Tumor AFP, positive CK-7, positive CK-7, negative Glypican-3, negative Glypican-3, positive HNF1-beta, positive HNF1-beta, positive SALL4, negative SALL4, positive
86 AFP Glypican-3
87 SALL-4
88
89 Dysgerminoma
90 Solid CCC Dysgerminoma Polyhedral nuclei w/ inconspicuous nucleoli Lymphocytes and plasma cells PLAP-negative OCT3/4-negative CK7-positive Central, rounded nuclei w/ 1-4 nucleoli Lymphocytes and granulomas PLAP-positive OCT3/4-positive CK7-negative
91 PLAP OCT 3/4
92
93
94 CCC Steroid cell tumor Unilateral Yellow Other CCC patterns Cytokeratin pos Inhibin neg Calretinin neg Unilateral Yellow Uniform pattern Cytokeratin? Inhibin pos Calretinin pos
95 Clear Cell Renal Cell Carcinoma
96 When To Actively Exclude RCC Prior history of renal cell carcinoma Suspicion of a retroperitoneal mass Family history or renal cell carcinoma or evidence of hereditary renal cell carcinoma syndrome von Hippel-Lindau Hereditary leiomyomatosis Rare, but need to keep in consideration
97 CCC Renal Cell CA PAX8+ PAX2+ (<10%) HNF1β+ Unilateral Endometriosis PAX8+ PAX2+ (77%) HNF1β+ May be bilateral Renal mass or history of RCC
98 In conclusion, H&E
99 Thanks
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